A strong genetic contribution to the spectrum of pervasive developmental disorders is widely accepted, yet genetic factors underlying a substantial portion of the heritability remain elusive. Recent successes in genetic studies of complex disorders have taken two divergent paths. The first has evaluated common variants using a genome wide association paradigm. This design has yielded progress in heterogeneous disease models such as inflammatory bowel disease and type II diabetes, but has been less successful in identifying risk loci for complex neuropsychiatric conditions such as schizophrenia. The second has used advancing technology to invoke the rare variant hypothesis of common disease. Structural variations resulting in a net gain or loss of genetic material have been associated with several neuropsychiatric phenotypes in recent studies, suggesting that neurodevelopment pathways may be particularly sensitive to gene dosage effects. It has become clear that a proportion of the genetic risk for autism spectrum disorders (ASD) is attributable to such genomic events, and the culmination of numerous ongoing studies of common polymorphisms and rare anomalies will likely provide important insight into a portion of genetic risk for ASDs. What is not clearly addressed by either approach is the opportunity presented by balanced chromosomal rearrangements. Estimates of the incidence of such events are substantially increased in ASD patients, yet their impact is largely unknown as current genotyping methods preclude accurate detection of these events. Failure to appropriately consider this subgroup of ASD patients potentially bypasses an important component of the disease variance and a complementary opportunity for determining causative pathways, particularly if it targets different genetic contributions than either common polymorphism or dosage variation. It is within this relatively unexplored space that we seek to contribute to understanding the genetic basis of ASD pathogenesis. We propose to use recent advances in "next-generation" sequencing to identify genes disrupted in ASD patients with apparently balanced chromosomal rearrangements. The methods will build upon innovations in cancer genetics, customizing them for analysis of abnormal germline karyotypes. Our evolving methodology will also facilitate detection of small copy number variations, another nebulous source of genomic variation that researchers are struggling to characterize. The proposal will also be set apart from current genomic efforts by conducting secondary molecular analysis to define the pathogenic mechanism of disease susceptibility rather than to speculate upon the pathogenicity solely from de novo status or from frequency of the genomic event in patient and control cohorts. The studies will begin with the rich resource currently available within our collaborations of a significant number of ASD patients with translocations identified by karyotype analysis and culminate in characterization of a series of future targets for biological and pharmacological investigation. PUBLIC HEALTH RELEVANCE: It has become clear that a proportion of the genetic risk for autism spectrum disorders (ASD) is attributable to both common polymorphisms and rare structural variations. What is not clearly addressed by current approaches is the opportunity presented by balanced chromosomal rearrangements. Estimates of the incidence of such events are substantially increased in ASD patients compared to the general population, yet their impact is largely unknown as current methodology precludes rapid and accurate detection of these genomic events. Failure to appropriately consider this subgroup of ASD patients potentially bypasses an important component of the disease variance and a complementary opportunity for determining causative pathways. It is within this relatively unexplored space that we seek to contribute to understanding the genetic basis of ASD pathogenesis. We propose to use recent advances in "next-generation" sequencing to identify genes disrupted in ASD patients with apparently balanced chromosomal rearrangements. The methodology will also enable assessment of small copy number variations, another seemingly intractable source of genetic variation. Secondary molecular analysis will then be used to define the pathogenic mechanisms rather than speculate on causation. The studies will begin with the rich resource currently available within our collaborations of a significant number of ASD patients with apparently overlapping rearrangement breakpoints identified by karyotype analysis and culminate in characterization of a series of future targets for biological and pharmacological investigation.